title: The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.
abstract: OBJECTIVE
  The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association.
  
  
  METHODS
  The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448).
  
  
  RESULTS
  Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05).
  
  
  CONCLUSIONS
  Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. Electronic address: s.prudente@css-mendel.it.
authors.forename: S
authors.initials: S
authors.lastname: Prudente
authors.forename: M
authors.initials: M
authors.lastname: Copetti
authors.forename: E
authors.initials: E
authors.lastname: Morini
authors.forename: C
authors.initials: C
authors.lastname: Mendonca
authors.forename: F
authors.initials: F
authors.lastname: Andreozzi
authors.forename: M
authors.initials: M
authors.lastname: Chandalia
authors.forename: R
authors.initials: R
authors.lastname: Baratta
authors.forename: F
authors.initials: F
authors.lastname: Pellegrini
authors.forename: L
authors.initials: L
authors.lastname: Mercuri
authors.forename: D
authors.initials: D
authors.lastname: Bailetti
authors.forename: N
authors.initials: N
authors.lastname: Abate
authors.forename: L
authors.initials: L
authors.lastname: Frittitta
authors.forename: G
authors.initials: G
authors.lastname: Sesti
authors.forename: J C
authors.initials: JC
authors.lastname: Florez
authors.forename: A
authors.initials: A
authors.lastname: Doria
authors.forename: V
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D019317:Evidence-Based Medicine; D056726:Genetic Association Studies; D056426:Genetic Loci; D044882:Glucose Metabolism Disorders / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C518910:SH2B1 protein, human
keywords: Glucose homeostasis; Obesity; SH2B1; SNP; Type 2 diabetes